呼吸

难治性中性粒细胞性哮喘与纤毛基因

作者:孟爱宏 孙同欣玮 来源:南山呼吸 日期:2022-09-20
导读

         难治性哮喘(RA)患者占哮喘病人的3%-10%,占哮喘相关医疗保健利用率的60%以上,尽管坚持以指南为基础的治疗,但其症状控制仍较差。研究发现,与健康对照组(C)或非难治性哮喘(NR)患者相比,RA患者的呼吸道促嗜中性粒细胞增多,这与亚临床感染/炎症(SBI)有关,其潜在机制尚不清楚。

        研究背景

        难治性哮喘(RA)患者占哮喘病人的3%-10%,占哮喘相关医疗保健利用率的60%以上,尽管坚持以指南为基础的治疗,但其症状控制仍较差。研究发现,与健康对照组(C)或非难治性哮喘(NR)患者相比,RA患者的呼吸道促嗜中性粒细胞增多,这与亚临床感染/炎症(SBI)有关,其潜在机制尚不清楚。

        研究发现

        1. 刷检和活检样本的比较发现RA刷检中有更多下调的差异表达基因

        刷检和活组织检查样本有151个重叠的差异表达基因(DEG),其中141个在RA中下调,10个上调。下调基因中110个已知富含纤毛或成熟的纤毛细胞,82个被鉴定为早期纤毛、晚期纤毛或成熟纤毛状态,35个在纤毛细胞中具有功能验证的作用。

        2. 等级聚类法确定纤毛相关基因表达减少和呼吸道炎症增加的RA亚组

        刷检和活检数据的单独聚类分析显示,在刷检或活检样本中,有一组RA(34名受试者)纤毛细胞基因下调,将其标记为纤毛缺陷RA(CDRA)。经年龄、性别、BMI和口服皮质类固醇(OCS)调整后,CDRA与其他RA受试者相比,有更高的SBI几率;更高的血液、活检和支气管肺泡灌洗液(BALF)嗜酸性粒细胞;以及更高的BALF中性粒细胞。

        回顾60名RA受试者中58名的胸部CT报告,并根据“粘液”、“支气管扩张”或“树芽”描述的表现进行分类。34名CDRA受试者中有23人至少有1项发现。26名非CDRA受试者中,24名有CT报告,只有8人有描述的模式,这表明纤毛相关基因减少与具有临床意义的气道粘液模式增加有关。

        3. 加权基因相关网络分析加强DEG分析

        加权基因相关网络分析(WGCNA)的发现类似于差异表达分析,发现与纤毛功能相关的共表达网络在RA和其他RA之间存在显著差异。WGCNA对刷检和活检的数据分析显示,下调的基因模块富含与纤毛组装、组织和运动相关的基因,而大多数上调的模块富含与免疫反应相关的基因。

        结 论

        尽管该项研究具有局限性和探索性,但研究者们确定了一个独特的、临床上重要的纤毛缺陷难治性哮喘亚群。纤毛相关基因的表达减少与较高的粘液负担和亚临床细菌感染有关,可能是哮喘难以治疗的原因之一。

        讨 论

        1. 负责纤毛细胞分化、轴丝形成和定向运动的基因在我们称为CDRA的RA亚群中下调。这一亚组更有可能出现SBI、CT影像上较高的呼吸道炎症和较低的FEV1。据研究者所知,他们首次将CDRA描述为难治性中性粒细胞性哮喘的一个亚群。

        2. 这项研究有几个局限性。(1)基因表达的群体差异也可能受到哮喘,特别是RA自然病史的影响。虽然在分析中根据年龄进行了调整,但与NR相比,RA的年龄更高,病情恶化的几率更高。(2)所有NR患者都在接受吸入皮质类固醇(ICS)治疗,剂量差异可能会潜在影响结果,其他研究小组已经发现ICS可以改变呼吸道上皮基因的表达。然而,作者注意到CDRA组甚至与另一组RA组相比纤毛相关基因的表达显著减少,尽管这两组具有相似的临床特征、病情恶化、OCS接收和统一的高ICS剂量。(3)对于大量的基因表达数据,作者不能完全肯定地说,CDRA组纤毛相关基因的下调是由于CDRA纤毛细胞表达受抑,还是由于纤毛细胞丢失;然而,这两种情况中的任何一种都可能表明纤毛功能受损,并导致难治性。

        3. 未来的研究还应纠正吸入类固醇和β-激动剂对纤毛基因表达和功能的影响。临床上相关的纤毛失调特征也需要在包括T2和非T2哮喘的机制研究中得到证实。更高的SBI、更高的粘液负荷、CT的支气管壁扩张和增厚影像,以及纤毛失调导致的呼吸道清除不良,都可能致使CDRA中哮喘控制更差,需要进一步的系统研究。

        4. 鼻腔上皮细胞的基因表达谱与下呼吸道上皮细胞的基因表达谱有很大重叠。鼻腔上皮细胞纤毛相关基因可通过实时定量聚合酶链式反应或免疫染色进行检测。作者预计鼻腔上皮细胞纤毛相关基因的表达会较低。如果得到证实,那么鼻拭子的检查可以帮助指导CDRA类型的检测和通过基因表达谱分析治疗反应。

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